Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies.Analyses of a case-control study of 718 non-Hispanic white patients with cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco showed modest, non-significant decreased risk of melanoma among susceptible individuals who used sunscreens most of the time. Young women were the individuals most likely to use tanning beds, and use was related to melanoma risk. Those who used tanning beds were more likely to have melanomas in sites not usually exposed to sun. These observations may help explain the increasing rates and changing distribution of melanoma among young women in the general population. Questionnaire data, tumor, and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy, showed a strong association between germline variants in the melanocortin-1 receptor (MC1R) gene and melanoma with somatic mutations in the BRAF oncogene, in subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage. We confirmed this association in an independent population. Data from other Mediterranean populations have been collected and harmonized to extend the analyses of association between melanoma risk and several risk factors, also including immune-related genes. In this combined sample, we identified suggestive evidence for a role of telomere-related genes in the etiology of melanoma. Moreover, a genome-wide association study (GWAS) of melanoma cases from Mediterranean countries and appropriate controls is ongoing. A polygenic risk score analysis using the GWAS data and additional data from melanoma consortia is also ongoing. Melanoma tissue specimens have been collected and analyses of melanoma lesions in relation to sun exposure, body site, nevi count, susceptibility genes and molecular alterations is planned. One of the potential pathways that leads to the development of melanoma includes the loss of regulation of common melanocytic nevi, which acquire atypic or dysplastic characteristics that can further evolve in neoplasia. To study this pathway, we are currently collecting multiple tissue samples of normal skin, common melanocytic nevi, dysplastic nevi, melanoma and metastasis from melanoma from the same subjects from Italy and Spain. We are planning to study the expression and presence of mutations in multiple genes of the cell cycle, and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi. Chordoma is a rare primary malignant bone tumor that arises mainly in the axial skeleton from rests of embryonic notochordal stem cells that failed to undergo normal regression. A project was developed to collect personal and family medical history, buccal cells and tumor tissue from sporadic chordoma patients from the United States and Canada. Using DNA from 100 sporadic chordoma patients in this study, we identified several common and rare variants in the T gene that are related to disease risk, providing more evidence for the importance of the T gene in the pathogenesis of both familial and sporadic chordoma. Currently, we are using whole-exome sequencing (WES) to identify additional susceptibility genes in chordoma families without T duplication and sporadic chordoma cases. The WES analysis identified several genes that are potentially related to chordoma predisposition and functional follow-up is in process. We are also collaborating with cancer hospitals in Beijing, China to collect germline DNA and chordoma tumor tissues from Chinese chordoma patients to follow up on variants we identify from the WES project. Alterations in the normal microbiome are increasingly recognized to play a role in human disease. Using protocols adapted from the NIH Human Microbiome Project, we conductedpilot studies with investigators from the School of Medicine and Dentistry, University of Rochester to evaluate differences in the oral microbiome between smokers and nonsmokers. Analysis of the resultant microbiome data is in progress. Using data we collected from the Polish Breast Cancer Study and breast cancer association consortium, we demonstrated that risk factors for breast cancer and morphology and molecular characteristics of terminal duct lobular units (TDLUs), the structures from which breast cancers arise, varied by molecular subtypes. In addition, we found that parity-related molecular changes were preserved in breast cancer patients with ER-positive tumors but disrupted in patients with ER-negative tumors, a finding that may partially account for the observed differential effect of parity in these two tumor subtypes. We are currently analyzing the expression profiling data to identify molecular signatures for TDLU involution and parity. Recently, we initiated several breast cancer projects with clinicians and epidemiologists in Asian countries to study breast cancer among Asian women. Using data collected from Sarawak, Malaysia, we showed that the overrepresentation of early-onset and ER-negative tumors among Malaysian women was largely due to the disproportionally lower incidence of late-onset ER-positive tumors rather than an absolute increase in ER-negative cancers. We extended this finding using cancer registry data from several Asian countries (Singapore, Taiwan, Hong Kong, China, Korea) and reported that, after the adjustment of period and cohort effects, the age effects of breast cancer may be more similar between Asian and Western women than previously recognized. Our results also showed that rapidly rising cohort specific rates have narrowed the historic disparity between Chinese and US NHW breast cancer populations, particularly in regions with the lowest baseline rates (such as rural China) and among older women. We developed a new tissue-based breast cancer study in Hong Kong, and plan to collect breast tumor and adjacent normal tissues from up to 1,000 breast cancer cases with the goal of identifying molecular changes that are related to risk and clinical factors for breast cancer subtypes among Chinese women in Hong Kong. Using the Hong Kong data we collected, we found a complex relationship between tea drinking and breast cancer risk that is modified by menopausal status, age at tea drinking, and possibly ER status. We also identified an interesting association between nighttime eating and increased breast cancer risk among Hong Kong women.We are continuing to conduct studies of hematologic malignancies using the Swedish linked registry data to complement the family studies in GEB. However, the current level of activity of these studies is low. We have recently completed a study with some additional data added which describes the effect of prior autoimmune diseases on survival of patients with MGUS and multiple myeloma (MM). As expected, in control individuals, autoimmune diseases lower overall survival. We also found that survival of MGUS and MM patients was decreased in patients with pre-existing autoimmune diseases. When analyzing different types of autoimmune diseases, a history of ulcerative colitis had a stronger impact on survival in MM than in controls. Our findings that a history of autoimmune disease has a negative impact on survival in MM and MGUS could be due to shared underlying common genetic factors, or that patients with a personal history of autoimmunity develop more severe cases of MM and MGUS, or cumulative comorbidity in the individual. Our results suggest that more attention should be paid to comorbidity as a prognostic factor in MGUS and MM, and underlines the need for studies aimed at tailoring therapy according to comorbidity.